The present invention relates generally to methods and compositions for locally inhibiting release of selected endogenous compounds, as might be particularly useful for inhibiting glutamate and aspartate release in central nervous system loci.
Therapeutic treatment of various central nervous system disorders has been difficult to achieve because of the failure to provide sustained drug delivery. For example, Thyrotropin-releasing hormone (TRH), an endogenous central nervous system tripeptide, as well as TRH analogs, have been shown to have effective but transient anticonvulsant effects in a variety of animal seizure models. Nevertheless, therapeutic treatment utilizing TRH has been previously unsuccessful in the treatment of epilepsy. In this regard, patients suffering intractable seizures benefited only briefly from repeated TRH and TRH analog treatment.
In particular, oral and injected delivery of TRH and other neural peptides as therapeutic agents have been inadequate because of poor penetration of the drug to the desired site. Contributing factors to the limited site-specific bioavailability of therapeutic agents in the central nervous system include rapid peripheral metabolism, poor intestinal absorption, insufficient blood brain barrier penetration, inability to use synthetic precursors, and untoward side effects. As a result, delivering the neural peptide systemically by way of general circulation and/or cerebrospinal fluid would undesirably distribute the neural peptide to nonspecific receptor sites, thereby causing untoward side effects both systemically as well as in the central nervous system.
In U.S. Pat. No. 5,360,610, Tice et al. disclose polymeric microspheres, having diameters ranging from 5 to 45 micrometers, as injectable, drug-delivery systems for delivering bioactive agents to sites within the central nervous system. However, the injectable microspheres described by Tice et al. are ill-suited to provide sustained drug delivery to central nervous system loci because the microspheres tend to disperse in extracellular cerebrospinal fluid (CSF) and are subject to nonspecific uptake and delivery to more distant sites in the brain by CSF through the circumventricular organs, glia and neurons themselves. Larger microspheres are also inadequate because of insufficient rate of release of the bioactive agent from the interior of the microsphere to the site to be treated.
Other prior art approaches have involved use of lipophilic analogs of known neuropeptides, or lipophilic organic look-a-like compounds at a high affinity neuropeptide binding site to mimic endogenous neuropeptide activity, in the hope of enhancing drug delivery to promote long-lasting effects. However, these approaches have been ineffective because of widespread distribution of the neuropeptide analog to non-targeted receptor sites resulting in untoward side effects. In addition, other previous attempts have included osmotic minipumps, attachment to liposomes and cerebroventricular infusion. These attempts have also been ineffective because osmotic minipumps need replenishment, can become clogged and are a source of potential cerebral infection. Liposome attachment results in widespread distribution including non-targeted receptor sites resulting in untoward side effects. Cerebroventricular infusion results in a short duration of action and widespread distribution to non-targeted receptor sites leading to side-effects.
From the foregoing, it will be appreciated that there exists a need in the art for site-specific drug delivery to central nervous system loci in which sustained release of the drug is achieved without dispersion of the drug from the original site of implantation which causes nonspecific uptake and delivery to non-targeted receptor sites. It will be appreciated that there also exists a need in the art for site-specific drug delivery in which the release of the drug can be sustained at a relatively constant rate if desired.